The majority of American Indian (Al) families living in urban areas experience disproportional health disparities associated with substance abuse. These health disparities affect Al youth through higher rates, earlier initiation, and more severe consequences of substance use. The rapidly growing population of urban Al families is served by few evidence-based prevention approaches that are culturally grounded and reflective of specific socio-environmental forces shaping urban Al communities. Family disruption and substance abuse, stresses related to moving to urban settings, and difficulties in establishing and sustaining social and cultural connections frequently are mentioned as contributing to adverse health outcomes for urban Al youth. Using ecodevelopmental theory, this research will address gaps in knowledge of how contextual influences operating at peer, family/parental, school, and neighborhood levels influence substance use among urban Al youth in Arizona. The study will document the relative influence of factors at these different levels using a comprehensive model, test how positive and negative family influences interact with those at other levels, and examine how they may operate differently in subgroups of urban Al youth defined by gender, grade level, and heritage that is Al-only or mixed Al and non-AI heritage. The research uses a 2010 state-wide survey of youth substance use with large numbers of urban Al youth (N=3,450) living in a range of urban communities that vary in size and migration histories. The proposed study draws upon the project team's research, conducted at an NIMHD Center of Excellence, on the social determinants of Al family behavioral health, salient risk and resiliency factors, culturally appropriate strategies for resisting risk behaviors, and systematic methods for culturally adapting prevention programs. The study is designed to bridge science to practice and policy via partnerships with governmental and community-based health organizations to provide mechanisms for interpreting and disseminating findings; providing a foundation for translational research. The study will create essential knowledge about how to target and deliver prevention interventions comprehensively by identifying issues that urban Al youth and families face in urban contexts.